The present invention relates to a novel method for administration of active substances to the olfactory region of the nose. The method is useful for the treatment of diseases affecting the olfactory organ, the brain and the central nervous system.
The transport of most bioactive materials from the systemic circulation to the brain are severely impeded by the mechanical and metabolic barrier known as the blood-brain-barrier. Only lipid-soluble molecules are able to enter the central nervous system in sufficient amounts, unless there are certain transport systems available. Due to this problem many drugs which do not cross this barrier, need to be injected directly into the subarachnoid space by lumbar puncture or cysternal puncture (Allison and Stach. Drug Intell. Clin. Pharm. 12;347:1978). Techniques for direct injection into the brain (intrathecal or subarachnoid injection) is associated with high risk for the patient, causing pain and hospitalisation, particularly in the case of repeated treatment. The method is poorly tolerated, requires the use of sterile syringes, may cause he risk of infection, induration, haemorrhage and/or slight necrosis at the injection site. The treatment is expensive and time consuming and may only be carried out by highly skilled personnel and in facilities that fulfil all requirements for brain surgeries.
The olfactory region has been the port for some serious infections as well as organic solvents, causing meningitis and brain damage, respectively. It has been shown that viruses, such as neurovirulent viruses, have been transported into the brain through the olfactory fibres and into the central nervous system. Other infections have been caused by Human erpetic encephalitis or the bacteria Hemophilus influenzae. Even parasites such as Naegleria fowleri are able to be transported across this area into the brain, causing death within 72 hours after infection (Lund et al. J. Neuropath. Exp. Neurol. 47;497:1988; Kristensson and Olsson. Acta Neuropath. 19;145:1971). The first evidence for a pathway between the olfactory mucosa and the central nervous system came from experiments with dyes, injected into the subarachnoid space of the brain passing into the nasal mucous membrane in low concentration (Yoffey. J. Laryng. 43;166:1949). Other substances were studied, which supported this theory, such as 32P labelled phosphoric acid (Orosz et al. Acta. Physiol. Acad. Sci. Hung. 11;75:1957), colloidal gold (198Au) (Czerniawska. Acta Otolaryng. 70;58:1970) and wheat germ agglutinin conjugated to horseradish peroxidase (Kristensen. Acta Neuropath. 19;145:1971). More recently it has been demonstrated that a direct transport of a bioactive material, such as insulin, occurs from the olfactory region of the nose to the brain (Gizurarson et al. Int. J. Pharm. 146;135:1997; and Gizurarson et al. Drug Delivery. in press).
WO 91/07947 describes the possibility for transporting neurologic and/or diagnostic neurologic agents to the brain by means of the olfactory neural pathway. WO 91/07947 also describes pharmaceutical compositions useful in the treatment and diagnosis of brain disorders.
WO 97/16181 relates to a method for enhancing the delivery of L-dopa to the brain of a mammal by administering water-soluble prodrugs of L-dopa intranasally.
U.S. Pat. No. 5,525,329 provides a method for enhancing the sense of smell involving application of an inhibitor of phosphodiesterase to the olfactory epithlium.
However, using the conventional techniques (such as described in e.g. WO 91/07947) for administration of drugs into the nasal cavity it has been found by the present inventor that it is nearly impossible to get access to the olfactory region. Nearly means, as will be apparent from the examples provided herein, that conventional spray techniques result in less than 0,4% of the formulation having access to the olfactory region. Furthermore, nasal drops and nasal catheter did not provide access to this region.
Clearly, there is a need for improved methods, including suitable nasal devices and suitable pharmaceutical preparations, for administering effective amounts of active substances to the olfactory region, thereby improving the possibility of administering active substances to the brain and to the central nervous system.
Thus, the main object of the present invention is to provide a method for administering active substances to the olfactory region of a human in clinically relevant amounts.
These and other goals are met by the present invention which in a first aspect is directed to a method for administering a pharmaceutical preparation comprising at least one active substance to the olfactory region of a human, the method comprising administering a unit dose of the pharmaceutical preparation by ejection from a nozzle of a spray device through a nostril of the human, the device being positioned so that the exit orifice of the nozzle is positioned approximately at the orifice of the nostril or in the vestibulum nasi, the device and the pharmaceutical preparation being adapted so that the spray angle is at the most 35xc2x0.
Another aspect of the invention relates to a nasal spray device containing an amount of a pharmaceutical preparation and being adapted for ejecting a unit dose of the pharmaceutical preparation from a nozzle of the spray device through a nostril of a human on actuation of the device, the device and the pharmaceutical preparation being adapted so that the spray angle is at the most 35xc2x0.
A further aspect of the invention relates to a nasal spray device containing an amount of a pharmaceutical preparation and being adapted for ejecting a unit dose of the pharmaceutical preparation from a nozzle of the spray device through a nostril of a human on actuation of the device, the pharmaceutical preparation being a liquid having a dynamic viscosity at 25xc2x0 C. in the range of 5-300 cP.
Further aspects appear from the claims and the following description.